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Circadian SCN-Liver Axis in the Neuroendocrine Response to Calorie Restriction

Award Number: R01DK132647
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Circadian SCN-Liver Axis in the Neuroendocrine Response to Calorie Restriction - In mammals, the hypothalamic pacemaker clock synchronizes peripheral tissue clocks to temporally partition oxidative and reductive metabolic pathways to align fuel utilization with nutrient availability. Yet how the circadian clock in brain and peripheral tissues integrates nutrient state with transcription to promote energy conservation and metabolic homeostasis during sleep and in nutrient scarce conditions remains obscure. An exciting clue as to how nutrient signals control circadian transcription emerged from the discovery in our group and others that nicotinamide adenine dinucleotide (NAD+) and the NAD+-dependent deacetylase SIRT1 regulate circadian behavioral and mitochondrial rhythms through posttranslational modification of the core clock repressor PER2, indicating that NAD+-SIRT1 controls clock cycles within both neurons and peripheral cells. Interconversion of NAD+ with its reduced form NADH during redox reactions is dependent upon nutrient state. In new results published after our first submission, we show that NADH accumulation in liver during healthful calorie restriction inhibits SIRT1 and reduces daytime body temperature and oxidative metabolism. Surprisingly, reducing NADH levels through hepatic transduction of the water-forming NADH oxidase Lactobacillus brevis (LbNOX) disinhibits SIRT1 and augments oxidative cycles of metabolism and transcription. Further, our newly-generated PER2K680Q acetyl-mimetic knockin mice, which are resistant to SIRT1-induced deacetylation, exhibit profound period lengthening, while clock ablation in the suprachiasmatic nucleus (SCN) abrogates rhythmic feeding and thermogenesis. We are now poised with innovative genetic tools and circadian protocols to dissect how the circadian clock promotes energy constancy during sleep and in adaptation to calorie restriction at the level of the liver (Aim 1) and hypothalamic pacemaker neurons (Aim 2). Aim 1 will specifically test the hypothesis that nutrient sensing by the clock involves NAD(H)-SIRT1 signaling. We propose to dissect the role of redox state in clock function and metabolism during sleep and calorie restriction by genetically manipulating NAD(H) levels using LbNox in combination with hepatic clock ablation or PER2K680Q acetyl-mimetic knockin mice. Aim 2 will examine the role of hypothalamic pacemaker neuron subtypes in synchronizing thermogenesis, feeding, and metabolic rhythms with sleep and in the adaptive response to calorie restriction by utilizing an innovative combination of CRISPR-Cas9 clock ablation, loss and gain of function studies, and projection-based chemogenetic manipulation of pacemaker neurons. Collectively, our proposed studies will elucidate circadian mechanisms involved in maintenance of energy constancy across the sleep-wake cycle and how clock adaptations contribute to health benefits of hypocaloric diet.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $528,389 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/28/2026	NON-COMPETING CONTINUATION	$528,389
														Subtotal = $528,389

Issue Date FY: 2025 ( Subtotal = $528,389 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/20/2025	NON-COMPETING CONTINUATION	$475,551
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/14/2025	NON-COMPETING CONTINUATION	$52,838
														Subtotal = $528,389

Issue Date FY: 2024 ( Subtotal = $507,253 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/6/2024	NON-COMPETING CONTINUATION	$31,702
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/1/2024	NON-COMPETING CONTINUATION	$475,551
														Subtotal = $507,253

Issue Date FY: 2023 ( Subtotal = $528,389 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/1/2023	NEW	$528,389
														Subtotal = $528,389

Grand Total All Awards = $2,092,420

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Circadian SCN-Liver Axis in the Neuroendocrine Response to Calorie Restriction

Award Number: R01DK132647

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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